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Abstract

Lipotoxicity, which is characterized by increased accumulation in cardiomyocytes of toxic lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. The present study tested the hypothesis that cardiac lipid overload alters mitochondrial dynamics leading to impaired mitochondrial energetics. We first examined an animal model of moderate lipid overload in the heart, namely mice with low-level overexpression (3-fold) of long chain acyl-CoA synthetase 1 (ACS1) driven by the cardiomyocyte-specific α-MHC promoter (ACStg mice). In these mice, palmitate distribution to the heart, measured by in vivo PET, was increased by 2-fold. Echocardiographic analysis showed normal fractional shortening with increased left ventricular wall thickness (29% increase), but +dP/dt was reduced by 11% (p<0.01). This 2-fold increase in palmitate uptake led to a striking fragmentation of the mitochondrial network, characterized by numerous small mitochondria and mitochondrial proliferation in cardiomyocytes, that was associated with decreased palmitoyl-carnitine oxidation in permeabilized fibers and increased mitochondrial ROS generation. The mitochondrial fusion and fission proteins, Optic-Atrophy type 1 (OPA1) and Dynamin-related protein 1 (Drp1) were dysregulated in ACStg mice. The inactive low molecular (shed) isoform of OPA1 was significantly increased by1.7-fold and post-translational modifications of Drp1 as evidenced by differential electrophoretic mobility was observed in the hearts of ACStg mice. To model these changes in vitro, we incubated neonatal rat ventricular cardiomyocytes (NRVMs) with 500μM palmitate and observed mitochondrial fragmentation that was not seen following incubation with oleate. In NRVMs, palmitate induced translocation of Drp1 to mitochondria that temporally preceded mitochondrial fragmentation. Taken together, these experiments strongly suggest that lipid overload profoundly alters the signaling pathways that regulate mitochondrial dynamics, revealing a novel mechanism for mitochondrial and cardiac dysfunction in lipotoxic cardiomyopathy.